Bridged and fused antidiabetic compounds

ABSTRACT

This invention provides for certain bridged and fused compounds of the formula G-L-A I or a pharmaceutically acceptable salt, ester of solvate thereof wherein: A is: (I) and the other variables are defined herein; the inventive compounds are agonists of the G-protein coupled receptor 40 (GPR40, also known as free fatty acid receptor FFAR). This invention further relates to pharmaceutical compositions containing these compounds, and the use of these compounds to regulate insulin levels in a mammal. The compounds may be used, for example in the prevention and treatment of Type 2 diabetes mellitus and in the prevention and treatment of conditions related to Type 2 diabetes mellitus, such as insulin resistance, obesity and lipid disorders.

RELATED APPLICATIONS

This application claim benefit of U.S. provisional application U.S. Ser.No. 61/146,868, filed Jan. 23, 2009, herein incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to certain bridged and fused compoundsthat are agonists of the G-protein coupled receptor 40 (GPR40, alsoknown as free fatty acid receptor FFAR), pharmaceutical compositionscontaining the compounds, and the use of these compounds to regulateinsulin levels in a mammal. The compounds may be used, for example inthe prevention and treatment of Type 2 diabetes mellitus and in theprevention and treatment of conditions related to Type 2 diabetesmellitus, such as insulin resistance, obesity and lipid disorders.

BACKGROUND OF THE INVENTION

Diabetes refers to a disease state or process derived from multiplecausative factors and is characterized by elevated levels of plasmaglucose (hyperglycemia) in the fasting state or after administration ofglucose during a glucose tolerance test. Persistent or uncontrolledhyperglycemia is associated with a wide range of pathologies. Diabetesmellitus, is associated with elevated fasting blood glucose levels andincreased and premature cardiovascular disease and premature mortality.It is also related directly and indirectly to various metabolicconditions, including alterations of lipid, lipoprotein, apolipoproteinmetabolism and other metabolic and hemodynamic diseases. As such, thediabetic patient is at increased risk of macrovascular and microvascularcomplications. Such complications can lead to diseases and conditionssuch as coronary heart disease, stroke, peripheral vascular disease,hypertension, nephropathy, neuropathy, and retinopathy. Accordingly,therapeutic control and correction of glucose homeostasis is regarded asimportant in the clinical management and treatment of diabetes mellitus.

There are two generally recognized forms of diabetes. In Type 1diabetes, or insulin-dependent diabetes mellitus (IDDM), the diabeticpatient's pancreas is incapable of producing adequate amounts ofinsulin, the hormone which regulates glucose uptake and utilization bycells. In Type 2 diabetes, or noninsulin dependent diabetes mellitus(NIDDM), patients often produce plasma insulin levels comparable tothose of nondiabetic subjects; however, the cells of patients sufferingfrom type 2 diabetes develop a resistance to the effect of insulin, evenin normal or elevated plasma levels, on glucose and lipid metabolism,especially in the main insulin-sensitive tissues (muscle, liver andadipose tissue).

Insulin resistance is not associated with a diminished number ofcellular insulin receptors but rather with a post-insulin receptorbinding defect that is not well understood. This cellular resistance toinsulin results in insufficient insulin activation of cellular glucoseuptake, oxidation, and storage in muscle, and inadequate insulinrepression of lipolysis in adipose tissue, and of glucose production andsecretion in the liver. A net effect of decreased sensitivity to insulinis high levels of insulin circulating in the blood without appropriatereduction in plasma glucose (hyperglycemia). Hyperinsulinemia is a riskfactor for developing hypertension and may also contribute to vasculardisease.

Patients who have insulin resistance often have several symptoms thattogether are referred to as Syndrome X, or the metabolic syndrome.According to one widely used definition, a patient having metabolicsyndrome is characterized as having three or more symptoms selected fromthe group of five symptoms: (1) abdominal obesity; (2)hypertriglyceridemia; (3) low high-density lipoprotein cholesterol(HDL); (4) high blood pressure; and (5) elevated fasting glucose, whichmay be in the range characteristic of Type 2 diabetes if the patient isalso diabetic. Each of these symptoms is defined clinically in the ThirdReport of the National Cholesterol Education Program Expert Panel onDetection, Evaluation and Treatment of High Blood Cholesterol in Adults(Adult Treatment Panel III or ATP III), National Institutes of Heath,2001, NIH Publication No. 01-3670. Patients with metabolic syndrome,whether or not they have increase risk of developing the macrovascularand microvascular complications that occur with Type 2 diabetes, such asatherosclerosis and coronary heart disease.

The available treatments for Type 2 diabetes, some of which have notchanged substantially in many years, are used alone and in combination.Many of these treatments have recognized limitations, however. Forexample, while physical exercise and reductions in dietary intake offat, high glycemic carbohydrates, and calories can dramatically improvethe diabetic condition, compliance with this treatment is very poorbecause of well-entrenched sedentary lifestyles and excess foodconsumption, especially of foods containing high amounts of saturatedfat. Increasing the plasma level of insulin by administration ofsulfonylureas (e.g. tolbutamide and glipizide) or meglitinide, whichstimulate the pancreatic beta-cells to secrete more insulin, and/or byinjection of insulin when sulfonylureas or meglitinide becomeineffective, can result in insulin concentrations high enough tostimulate insulin-resistance in tissues. However, dangerously low levelsof plasma glucose can result from administration of insulin or insulinsecretagogues (sulfonylureas or meglitinide), and an increased level ofinsulin resistance due to the even higher plasma insulin levels canoccur. The biguanides are a separate class of agents that can increaseinsulin sensitivity and bring about some degree of correction ofhyperglycemia. These agents, however, can induce lactic acidosis, nauseaand diarrhea.

The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are another classof compounds that have proven useful for the treatment of Type 2diabetes. These agents increase insulin sensitivity in muscle, liver andadipose tissue in several animal models of type 2 diabetes, resulting inpartial or complete correction of the elevated plasma levels of glucosewithout occurrence of hypoglycemia. The glitazones that are currentlymarketed are agonists of the peroxisome proliferator activated receptor(PPAR), primarily the PPAR-γ subtype. PPAR-γ agonism is generallybelieved to be responsible for the improved insulin sensititization thatis observed with the glitazones. Newer PPAR agonists that are beingtested for treatment of Type 2 diabetes are agonists of the alpha, gammaor delta subtype, or a combination thereof, and in many cases arechemically different from the glitazones (i.e., they are notthiazolidinediones). Serious side effects (e.g. liver toxicity) havebeen noted in some patients treated with glitazone drugs, such astroglitazone.

Compounds that are inhibitors of the dipeptidyl peptidase-IV (DPP-IV)enzyme are also under investigation as drugs that may be useful in thetreatment of diabetes, and particularly Type 2 diabetes.

Additional methods of treating hyperglycemia and diabetes are currentlyunder investigation. New biochemical approaches include treatment withalpha-glucosidase inhibitors (e.g. acarbose), protein tyrosinephosphatase-1B (PTP-1B) inhibitors, and glucagon receptor antagonists.

The free fatty acid receptor GPR40 (FFAR or FFAR1) is part of a familyof recently deorphanized GPCR's that bind fatty acids of varying chainlengths. GPR40 binds long-chain FFA, particularly oleate, as well as thePPAR-gamma agonist rosiglitazone. GPR40 is highly expressed in thepancreas, where it functions to produce insulin release upon agoniststimulation through activation of the PKC pathway resulting in Ca++efflux. The receptor is also expressed in throughout the brain inmonkeys and humans, but not in rodents.

Initial studies in GPR40 KO mice reported that they were resistant tohigh-fat diet-induced insulin resistance, suggesting an antagonistmechanism would be appropriate for this target. However, given thelocalization and function of the receptor, as well as the fact that mostgroups have not replicated this initial finding, the use of an agonistappears to be the appropriate answer for increasing insulin release forthe treatment of diabetes. In facts, it has been demonstrated thatagonists of GPR40 stimulate glucose-dependent insulin secretion in vitroand lower an elevated blood glucose level in vivo. See for example,Diabetes 2008, 57, 2211; J. Med. Chem. 2007, 50, 2807.

Compounds that act as GPR40 receptor agonists are known in the art.WO2008/054674 (assigned to Merck) discloses bicyclic derivatives of theformula

These derivatives are said to be useful in treating Type 2 diabetesmellitus and conditions associated with the disease, including insulinresistance, obesity and lipid disorders. WO2006/083781, WO2006/083612,US 2007/0265332 and WO2008/054674 (all assigned to Merck) disclosebicyclic derivatives that modulate the GPR40 receptor and are said totreat Type-2 diabetes.

Other bicyclic derivatives are known in the art to be useful in treatingdisease states such as diabetes, obesity and metabolic disorder. WO2004/058174 (assigned to Bayer) discloses indane acetic acid derivativesof the formula

and states that these derivatives are useful in treating Type-2diabetes, obesity and atherosclerotic diseases.

US 2005/0245529 (Boehringer Ingelheim) discloses alkyne derivatives thatare said to be useful in treating metabolic disorders and diabetes byantagonizing the MCH-receptor.

There is a need for new compounds, formulations, treatments andtherapies to treat diseases and disorders associated with the GPR40receptor that exhibit good safety profiles and efficacy by controllinginsulin levels in a mammal. It is, therefore, an object of thisinvention to provide compounds that are useful in the treatment orprevention or amelioration of diseases and disorders associated with theGPR40 receptor, such as hyperglycemia, diabetes, and related metabolicdiseases and indications.

SUMMARY OF THE INVENTION

In its many embodiments, the present invention provides for a novelclass of bridged and fused heterocyclic compounds that are agonists ofthe GPR40 receptor, or metabolites, stereoisomer, salts, solvates orpolymorphs thereof, methods of preparing such compounds, pharmaceuticalcompositions comprising one or more of such compounds, methods ofpreparing pharmaceutical formulations compromising one or more suchcompounds, and methods of treatment, prevention, inhibition oramelioration of one or more conditions associated with compounds thatact as agonists of the GRP40 receptor.

In one aspect, the present application discloses a compound, orpharmaceutically acceptable salts, esters, metabolites, solvates,prodrugs or polymorphs of said compound, said compound having thegeneral structure shown in the Formula:

G-L-A  I

or a pharmaceutically acceptable salt, ester of solvate thereofwherein

-   -   G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which are        optionally substituted by at least one (for example 1 to 5 or 1        to 3) R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   A is

-   -   W is —C— or —N—;    -   X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or        —N(R⁸)—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   Z is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl,            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl,wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,and cycloalkylalkoxy are optionally substituted with one or more (forexample 1 to 5 or 1 to 3) groups selected from the group consisting of—OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, andcycloalkyl;

R² is independently selected from the group consisting of halogen, —SF₅,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more (for example 1 to 5 or 1 to 3) groups selected from thegroup consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl,alkoxy, haloalkoxy, and cycloalkyl;

R³ is independently selected from the group consisting of H, alkyl andhaloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more (for example 1 to 5 or 1        to 3) R¹² moieties;

R⁸ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more (for example 1 to 5 or 1 to 3)groups selected from the group consisting of —OH, halo, alkyl,haloalkyl, alkoxy, haloalkoxy and cycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁰ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least one (forexample 1 to 5 or 1 to 3) substituents selected from the groupconsisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶ and R⁷ are independently unsubstituted orsubstituted by one or more (for example 1 to 5 or 1 to 3) R¹² groups,where

R¹² is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo and wherein each alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more (for example 1to 5 or 1 to 3) R¹³ groups where

-   -   R¹³ is independently selected from the group consisting of        alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,        heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵,        —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3,

provided that Y and Z cannot be a bond at the same time.

In another aspect, the present application provides for a pharmaceuticalcomposition comprising a pharmaceutically effective amount of compoundof Formula I or a pharmaceutically acceptable salt, ester, solvate orprodrug thereof and a pharmaceutically acceptable carrier.

In yet another aspect, the present application provides for a method forcontrolling insulin levels in a mammal (e.g., human) in need thereofwhich comprises administering an effective amount of a compound ofFormula I or a pharmaceutically acceptable salt, ester, solvate, orprodrug thereof to said mammal (e.g., human).

Another aspect of the present invention is to provide for a method forthe prevention or treatment of Type-2 diabetis mellitus in a mammal(e.g., human) in need thereof which comprises administering an effectiveamount of a compound of Formula I or a pharmaceutically acceptable salt,ester, solvate, or prodrug thereof to said mammal (e.g., human).

Another aspect of the present invention is to provide for a method forthe prevention or treatment of conditions related to Type-2 diabetismellitus (e.g., insulin resistance, obesity and lipid disorders) in amammal (e.g., human) in need there of which which comprisesadministering an effective amount of a compound of Formula I or apharmaceutically acceptable salt, ester, solvate, or prodrug thereof tosaid mammal (e.g., human).

Another aspect of the present invention is to provide for a method forthe prevention or treatment of Syndrome X in a mammal (e.g., human) inneed thereof which comprises administering an effective amount of acompound of Formula I or a pharmaceutically acceptable salt, ester,solvate, or prodrug thereof to said mammal (e.g., human).

DETAILED DISCUSSION

In an embodiment, the present invention discloses certain bridged andfused heterocyclic compounds that are represented by structural FormulaI, or a pharmaceutical acceptable salt, ester, solvate or prodrugthereof, wherein the various moieties are described above.

In one embodiment, the present invention discloses compounds of Formulaa, which are represented by the structural formula

or a pharmaceutically acceptable salt, ester, solvate or prodrugthereof,

-   -   G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is        optionally substituted by at least one R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   W is —C— or —N—;    -   X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or        —N(R⁸)—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   Z is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl,            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl,wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,and cycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

-   -   R² is independently selected from the group consisting of        halogen, —SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,        cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy,        aryl, arylalkyl, heteroaryl, heteroarylalkyl and        —S(O)_(q)-alkyl, wherein said alkyl, alkoxy, cycloalkyl,        cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,        arylalkyl, heteroaryl, and heteroarylalkyl are optionally        substituted with one or more groups selected from the group        consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl,        alkoxy, haloalkoxy, and cycloalkyl;

R³ is independently selected from the group consisting of H, alkyl andhaloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more R¹² moieties;

R⁸ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁰ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least onesubstituent selected from the group consisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶ and R⁷ are independently unsubstituted orsubstituted by one or more R¹² groups, where

-   -   R¹² is independently selected from the group consisting of        alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,        heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵,        —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅,        —CN, and halo and wherein each alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in        R¹² is independently unsubstituted or substituted by one or more        R¹³ groups where    -   R¹³ is independently selected from the group consisting of        alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,        heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵,        —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3,

provided that Y and Z cannot both be a bond at the same time.

In another embodiment, the present invention discloses compounds ofFormula I, which are represented by the structural Formula

or a pharmaceutically acceptable salt, ester, solvate or prodrugthereof,

-   -   G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is        optionally substituted by at least one R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   W is —C— or —N—;    -   X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or        —N(R⁸)—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   Z is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl,wherein said alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,and cycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R² is independently selected from the group consisting of halogen, —SF₅,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R³ is independently selected from the group consisting of H, alkyl andhaloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more R¹² moieties;

R⁸ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁹ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least onesubstituent selected from the group consisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶ and R⁷ are independently unsubstituted orsubstituted by one or more R¹² groups, where

-   -   R¹² is independently selected from the group consisting of        alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,        heteroarylalkyl, —OR⁴—C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵,        —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅,        —CN, and halo and wherein each alkyl, cycloalkyl,        cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,        heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in        R¹² is independently unsubstituted or substituted by one or more        R¹³ groups where    -   R¹³ is independently selected from the group consisting of        alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,        heterocycloalkyl, heterocycloalkylalkyl, heteroaryl,        heteroarylalkyl, —OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵,        —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3,

provided that Y and Z cannot both be a bond at the same time.

An embodiment of the present invention is a compound of Formula Ia whereW is —CH—.

Another embodiment of the present invention is a compound of Formula Iawhere X is a bond.

Another embodiment of the present invention is a compound of Formula Iawhere X is a —CH₂—.

Another embodiment of the present invention is a compound of Formula Iawhere X is a —O—.

Another embodiment is a compound of Formula Ia where Y is bond.

Another embodiment is a compound of Formula Ia where Y is —CH₂—.

Another embodiment is a compound of Formula Ia where Y is —CH₂—CH₂—.

Another embodiment is a compound of Formula Ia where Z is a bond.

Another embodiment is a compound of Formula Ia where Z is —CH₂—.

Another embodiment is a compound of Formula Ia where Z is —CH₂—CH₂—.

Another embodiment is a compound of Formula Ia where W is —CH— and R¹ ishalogen, cyano or —SF₅ and p is 1.

Another embodiment is a compound of Formula Ia where G is aryl; forexample, phenyl or naphthyl.

Another embodiment is where G is heteroaryl; for example, pyridyl,pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolyl,oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl,triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl,phthalazinyi, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl,benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl,thienopyrimidyl, isoquinolinyl, benzoazaindolyl, 1,2,4-triazinyl,benzothiazolyl.

Another embodiment is a compound of Formula Ia where G is phenyl ornaphthyl and R² is absent.

Another embodiment is a compound of Formula Ia where G is phenyl ornaphthyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia where G is pyrimidinyl,pyridyl, or thiazolyl and R² is absent.

Another embodiment is a compound of Formula Ia where G is pyrimidinyl,pyridyl, or thiazolyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia where R is —CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia where R is—CH₂—C(O)—C(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

and R⁸ is independently H or —(C₁-C₄)alkyl,

Another embodiment is a compound of Formula Ia where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

R⁸ is independently H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or—(C₁-C₄)alkyl,

Another embodiment is a compound of Formula Ia where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia where R is tetrazolyl.

Another embodiment is a compound of Formula Ia where L is —O—.

Another embodiment is a compound of Formula Ia where L is —N(R³)— and R³is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia where R² absent or R² isH, haloalkyl (e.g., trifluoromethyl) or halo.

An embodiment of the present invention is a compound of Formula Ib whereW is —CH—.

Another embodiment of the present invention is a compound of Formula Ibwhere X is a bond.

Another embodiment is a compound of Formula Ib where Y is —O—.

Another embodiment is a compound of Formula Ib where Y is —CH₂—.

Another embodiment is a compound of Formula Ib where Z is a bond.

Another embodiment is a compound of Formula Ib where Z is —O—.

Another embodiment is a compound of Formula Ib where Z is —CH₂—.

Another embodiment is a compound of Formula Ib where Y is a bond.

Another embodiment is a compound of Formula Ib where Y is —O—.

Another embodiment is a compound of Formula Ib where V is —CH₂—,

Another embodiment is a compound of Formula Ib where W is —CH— and R¹ ishalogen, cyano or —SF₅ and p is 1.

Another embodiment is a compound of Formula Ib where G is aryl; forexample, phenyl or naphthyl.

Another embodiment is a compound of Formula Ib where G is heteroaryl;for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, benzofurazanyl, indolyl,azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,thienopyridyl, quinazolinyl, thienopyrimidyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl.

Another embodiment is a compound of Formula Ib where G is phenyl ornaphthyl and R² is absent.

Another embodiment is a compound of Formula Ib where G is phenyl ornaphthyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ib where G is pyrimidinyl,pyridyl, or thiazolyl and R² is absent.

Another embodiment is a compound of Formula Ib where G is pyrimidinyl,pyridyl, or thiazolyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ib where R is —CH₂—C(O)—OH.Another embodiment is a compound of Formula Ib where R is—CH₂—C(O)—C(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ib where R is —CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ib where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

and R⁸ is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

R⁸ is independently H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or—(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is

R⁸ is H or —(C₁-C₄)alkyl and R¹¹ is R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib where R is tetrazolyl.

Another embodiment is a compound of Formula Ib where L is —O—.

Another embodiment is a compound of Formula Ib where L is —N(R³)— and R³is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ib where R² is absent or R²is H, haloalkyl (e.g., trifluoromethyl) or halo.

Another embodiment of the present invention is a compound of Formula Iaof the formula

or a pharmaceutically acceptable ester, salt, solvate or prodrug thereofwherein

-   -   G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is        optionally substituted by at least one R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   W is —C— or —N—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl,            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —S(O)_(q)-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy whereinsaid alkyl, alkoxy, cycloalkly, cycloalkyloxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, —S(O)_(q)-alkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R² is independently selected from the group consisting of halogen, —SF₅,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R³ is independently selected from the group consisting of H, alkyl,haloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more R¹² moieties;

R⁸ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁰ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least onesubstituent selected from the group consisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶, and R⁷ are independently unsubstituted orsubstituted by one or more R¹² groups, where

R¹² is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein each alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3.

An embodiment of the present invention is a compound of Formula Ia-1where W is —CH—.

Another embodiment is a compound of Formula Ia-1 where Y is a bond.

Another embodiment is a compound of Formula Ia-1 where Y is —CH₂—.

Another embodiment is a compound of Formula Ia-1 where Y is —CH₂—CH₂—.

Another embodiment is a compound of Formula Ia-1 where W is —CH— and R³is halogen, cyano or —SF₅ and p is 1.

Another embodiment is a compound of Formula Ia-1 where G is aryl; forexample, phenyl or naphthyl.

Another embodiment is a compound of Formula Ia-1 where G is heteroaryl;for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, benzofurazanyl, indolyl,azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,thienopyridyl, quinazolinyl, thienopyrimidyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl.

Another embodiment is a compound of Formula Ia-1 where G is phenyl ornaphthyl and R² is absent.

Another embodiment is a compound of Formula Ia-1 where G is phenyl ornaphthyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia-1 where G is pyrimidinyl,pyridyl, or thiazolyl and R² is absent.

Another embodiment is a compound of Formula Ia-1 where G is pyrimidinyl,pyridyl, or thiazolyl that is substituted by one or two R² groups, whichindependently are R² is haloalkyl (e.g., trifluorormethyl), —SF₅, cyanoor halo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia-1 where R is—CH₂—C(O)—OH. Another embodiment is a compound of Formula Ia-1 where Ris —CH₂—C(O)—C(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia-1 where R is—CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

and A⁸ is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-1 where L is —O—.

Another embodiment is a compound of Formula Ia-1 where L is —N(R³)— andR³ is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia-1 where R² is absent orR² is H, haloalkyl (e.g., trifluoromethyl) or halo.

Another embodiment is a compound of Formula Ia of the formula

or a pharmaceutically acceptable ester, salt, solvate or prodrug thereofwherein

-   -   G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is        optionally substituted by at least one R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   W is —C— or —N—;    -   X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or        —N(R⁸)—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl,            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —S(O)_(q)-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy whereinsaid alkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, —S(O)_(q)-alkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R² is independently selected from the group consisting of halogen, —SF₅,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R³ is independently selected from the group consisting of H, alkyl,haloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more R¹² moieties;

R^(B) is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁸, —S(O)_(q)-alkylene-OR⁴,S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁸,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁰ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least onesubstituent selected from the group consisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶, and R⁷ are independently unsubstituted orsubstituted by one or more R¹² groups, where

R¹² is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁸,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein each alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where

R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3.

An embodiment of the present invention is a compound of Formula Ia-2where W is —CH—.

Another embodiment is a compound of Formula Ia-2 where X is a bond.

Another embodiment is a compound of Formula Ia-2 where X is —CH₂—.

Another embodiment is a compound of Formula Ia-2 where X is —O—.

Another embodiment is a compound of Formula Ia-2 where Y is a bond.

Another embodiment is a compound of Formula Ia-2 where Y is —CH₂—.

Another embodiment is a compound of Formula Ia-2 where Y is —CH₂—CH₂—.

Another embodiment is a compound of Formula Ia-2 where W is —CH— and R³is halogen, cyano or —SF₅ and p is 1.

Another embodiment is a compound of Formula Ia-2 where G is aryl; forexample, phenyl or naphthyl.

Another embodiment is a compound of Formula Ia-2 where G is heteroaryl;for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, benzofurazanyl, indolyl,azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,thienopyridyl, quinazolinyl, thienopyrimidyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl.

Another embodiment is a compound of Formula Ia-2 where G is phenyl ornaphthyl and R² is absent.

Another embodiment is a compound of Formula Ia-2 where G is phenyl ornaphthyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia-2 where G is pyrimidinyl,pyridyl, or thiazolyl and R² is absent.

Another embodiment is a compound of Formula Ia-2 where G is pyrimidinyl,pyridyl, or thiazolyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ia-2 where R is—CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ia-2 where R is—CH₂—C(O)—C(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ia-2 where R is—CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ia-2 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

and R⁸ is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ia-2 where L is —O—. Anotherembodiment is a compound of Formula Ia-2 where L is —N(R³)— and R³ is Hor (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ia-2 where R² is absent orR² is haloalkyl (e.g., trifluoromethyl) or halo.

Another embodiment of the present invention is a compound of Formula Ib

or a pharmaceutically acceptable ester, salt, solvate or prodrug thereofwherein

-   -   G is aryl, aryl alkyl, heteroaryl, or heteroarylalkyl, which is        optionally substituted by at least one R²;    -   L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—;    -   W is —C— or —N—;    -   X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or        —N(R⁸)—;    -   Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),        —[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—;    -   R is a group selected from the group consisting of

-   -   and        -   (v) tetrazolyl,            -   wherein                -   Q is —CH— or —N—, and                -   J is —S—, —CH₂—, —O— or —N(R⁸)—;

R^(a) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R^(b) is independently selected from the group consisting of H, —OH,halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl;

R¹ is independently selected from the group consisting of H, halogen,—SF₅, —S(O)_(q)-alkyl, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy whereinsaid alkyl, alkoxy, cycloalkylalkoxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, —S(O)_(q)-alkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R² is independently selected from the group consisting of halogen, —SF₅,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;

R³ independently selected from the group consisting of H, alkyl,haloalkyl;

R⁴ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁵ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

R⁶ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;

R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl;

-   -   or R⁶ and R⁷ together form a 4- to 7-membered heterocycloalkyl        or a 5- or 5-membered heteroaryl ring optionally having, in        addition to the N atom, 1 or 2 heteroatoms selected from the        group consisting of O, N(R⁸), N or S, wherein said rings are        optionally substituted by one or more R¹² moieties;

R⁸ is independently selected from the group consisting of

H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—C(O)—R⁵, —C(O)O—R⁵, —C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴,—C(O)-alkylene-N(R⁶)(R⁷), —C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵,—S(O)_(q)-alkylene-OR⁴, —S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴,-alkylene-S(O)_(q)—R⁵, -alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) whereinsaid alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl andalkylene are optionally substituted with one or more groups selectedfrom the group consisting of —OH, halo, alkyl, haloalkyl, alkoxy,haloalkoxy and cycloalkyl;

R⁹ is independently selected from the group consisting of H, alkyl,haloalkyl;

R¹⁰ is independently selected from the group consisting of H, —OH,alkyl, alkyl, cycloalkyl or alkoxy wherein said alkyl, alkyl, cycloalkylor alkoxy groups are optionally substituted with at least onesubstituent selected from the group consisting of halo and —OR⁵;

R¹¹ is independently selected from the group consisting of H, alkyl, andhaloalkyl;

wherein each of the alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkylgroups in R⁴, R⁵, R⁶, and R⁷ are independently unsubstituted orsubstituted by one or more R¹² groups, where

R¹² is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein each alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where

R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵—S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅,—CN, and halo;

m is independently 1, 2, or 3;

n is independently 0, 1 or 2;

q is independently 0, 1, or 2; and

p is 0, 1, 2, or 3.

An embodiment of the present invention is a compound of Formula Ib-1where W is —CH—.

Another embodiment is a compound of Formula Ib-1 where X is a bond.

Another embodiment is a compound of Formula Ib-1 where X is —CH₂—.

Another embodiment is a compound of Formula Ib-1 where X is —O—.

Another embodiment is a compound of Formula Ib-1 where Y is a bond.

Another embodiment is a compound of Formula Ib-1 where Y is —CH₂—.

Another embodiment is a compound of Formula Ib-1 where Y is —CH₂—CH₂—.

Another embodiment is a compound of Formula Ib-1 where W is —CH— and R¹is halogen, cyano or —SF₅ and p is 1.

Another embodiment is a compound of Formula Ib-1 where G is aryl; forexample, phenyl or naphthyl.

Another embodiment is a compound of Formula Ib-1 where G is heteroaryl;for example, pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl,isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl,pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl,pyridazinyl, quinoxalinyl, phthalazinyl, benzofurazanyl, indolyl,azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl,thienopyridyl, quinazolinyl, thienopyrimidyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl.

Another embodiment is a compound of Formula Ib-1 where G is phenyl ornaphthyl and R² is absent.

Another embodiment is a compound of Formula Ib-1 where G is phenyl ornaphthyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ib-1 where G is pyrimidinyl,pyridyl, or thiazolyl and R² is absent.

Another embodiment is a compound of Formula Ib-1 where G is pyrimidinyl,pyridyl, or thiazolyl that is substituted by one or two R² groups, whichindependently are haloalkyl (e.g., trifluorormethyl), —SF₅, cyano orhalo (e.g., fluoro or chloro).

Another embodiment is a compound of Formula Ib-1 where R is—CH₂—C(O)—OH.

Another embodiment is a compound of Formula Ib-1 where R is—CH₂—C(O)—C(C₁-C₄) alkyl.

Another embodiment is a compound of Formula Ib-1 where R is—CH₂—C(O)—NH₂.

Another embodiment is a compound of Formula Ib-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib-1 where R is

and R⁸ is independently H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib-1 where R is

and R⁸ is H or —(C₁-C₄)alkyl.

Another embodiment is a compound of Formula Ib-1 where L is —O—.

Another embodiment is a compound of Formula Ib-1 where L is —N(R³)— andR³ is H or (C₁-C₄)alkyl or halo-(C₁-C₄)-alkyl.

Another embodiment is a compound of Formula Ib-1 where R² is absent orR² is haloalkyl (e.g., trifluoromethyl) or halo.

A further embodiment of the present invention is a compound selectedfrom the group consisting of

or a pharmaceutically acceptable ester, salt, or solvate thereof.

A further embodiment of the present invention is compounds of Formula Iin isolated and purified form.

A further embodiment of the present invention is the use of a compoundof Formula I or a pharmaceutically acceptable salt, ester, solvate orprodrug thereof in the manufacture of a medicament for the treatment ofType 2 diabetes mellitus.

A further embodiment of the present invention is the use of a compoundof Formula I or a pharmaceutically acceptable salt, ester, solvate orprodrug thereof in the manufacture of a medicament for the treatment ofdiseases associated with Type 2 diabetes mellitus (for example, insulinresistance, obesity and lipid disorders).

A further embodiment of the present invention is the use of a compoundof Formula I or a pharmaceutically acceptable salt, ester, solvate orprodrug thereof in the manufacture of a medicament for the treatment ofSyndrome X.

As used above, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. The term “substitutedalkyl” means that the alkyl group may be substituted by one or moresubstituents which may be the same or different, each substituent beingindependently selected from the group consisting of halo, alkyl, aryl,cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, —NH(alkyl),—NH(cycloalkyl), —N(alkyl)₂, carboxy and —C(O)O-alkyl. Non-limitingexamples of suitable alkyl groups include methyl, ethyl, n-propyl,isopropyl and t-butyl.

“Alkylene” means a dialent alkyl group; e.g —CH₂— (methylene) or—CH₂CH₂-(ethylene). The hydrogen groups may be replaced by one or moreof the alkyl substituents defined for alkyl above.

“Aryl” means an aromatic monocyclic or multicyclic ring system, in whichat least one of the multicyclic rings is an aryl ring, comprising about6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.The aryl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein. Non-limiting examples of suitable aryl groups includephenyl and naphthyl. Non-limiting examples of aryl multicyclic ringsystems include:

“Heteroaryl” means an aromatic monocyclic or multicyclic ring system, inwhich at least one of the multicyclic rings is aromatic, comprisingabout 5 to about 14 ring atoms, preferably about 5 to about 10 ringatoms, in which one or more of the ring atoms is an element other thancarbon, for example nitrogen, oxygen or sulfur, alone or in combination.Preferred heteroaryls contain about 5 to about 6 ring atoms. The“heteroaryl” can be optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

Non-limiting examples of heteroaryl multicyclic ring systems systemsinclude:

“Aralkyl” or “arylalkyl” means an aryl-alkyl-group in which the aryl andalkyl are as previously described. Preferred aralkyls comprise a loweralkyl group. Non-limiting examples of suitable aralkyl groups includebenzyl, 2-phenethyl and naphthalenylmethyl. The bond to the parentmoiety is through the alkyl.

“Alkylaryl” means an alkyl-aryl-group in which the alkyl and aryl are aspreviously described. Preferred alkylaryls comprise a lower alkyl group.Non-limiting example of a suitable alkylaryl group is tolyl. The bond tothe parent moiety is through the aryl.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined above. Non-limiting examples of suitable monocycliccycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyland the like. Non-limiting examples of suitable multicyclic cycloalkylsinclude 1-decalinyl, norbornyl, adamantyl and the like.

“Cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyland alkyl are as previously described. Preferred cycloalkylalkylscomprise a lower alkyl group.

“Halogen” and “Halo” mean fluorine, chlorine, bromine, or iodine.Preferred are fluorine, chlorine or bromine, and more preferred arefluorine and chlorine.

“Ring system substituent” means a substituent attached to an aromatic ornon-aromatic ring system which, for example, replaces an availablehydrogen on the ring system. Ring system substituents may be the same ordifferent, each being independently selected from the group consistingof aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, alkylheteroaryl,hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo,nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl,aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl,alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio,cycloalkyl, heterocyclyl, Y₁Y₂N—, Y_(I)Y₂N-alkyl-, Y₁Y₂NC(O)— andY₁Y₂NSO₂—, wherein Y₁ and Y₂ may be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, and aralkyl.

“Heterocycloalkyl” or “heterocyclyl” means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 10 ring atoms, in which one ormore of the atoms in the ring system is an element other than carbon,for example nitrogen, oxygen or sulfur, alone or in combination. Thereare no adjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclyls contain about 5 to about 6 ring atoms. Theprefix aza, oxa or thia before the heterocyclyl root name means that atleast a nitrogen, oxygen or sulfur atom respectively is present as aring atom. Any —NH in a heterocyclyl ring may exist protected such as,for example, as an —N(Boc), —N(CBz), —N(Tos) group and the like; suchprotected moieties are also considered part of this invention. Theheterocyclyl can be optionally substituted by one or more “ring systemsubstituents” which may be the same or different, and are as definedherein. The nitrogen or sulfur atom of the heterocyclyl can beoptionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl, tetrahydrofuranyl,tetrahydrothiophenyl, imidazolidinyl, pyrazolidinyl and the like.

It should be noted that in saturated heterocyclyl containing systems ofthis invention, there are no hydroxyl, amino, or thiol groups on carbonatoms adjacent to a N, O or S atom. Thus, for example, in the ring:

there is no —OH attached directly to carbons marked 2 and 5. It shouldalso be noted that this definition does not preclude (═O), (═S), or (═N)substitutions, or their tautomeric forms, on C atoms adjacent to a N, Oor S. Thus, for example, in the above ring, (═O) substitution on carbon5, or its imino ether tautomer is allowed.

Non-limiting examples which illustrate the present invention are asfollows:

The following non-limiting examples serve to illustrate radicals notcontemplated by the present invention:

“Heteroarylalkyl” or “heteroaralkyl” means a heteroaryl-alkyl-group inwhich the heteroaryl and alkyl are as previously described. Preferredheteroaralkyls contain a lower alkyl group. Non-limiting examples ofsuitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl.The bond to the parent moiety is through the alkyl.

“Heterocycloalkylalkyl” means a heterocycloalkyl-alkyl group in whichthe heteroalkyl and the alkyl are as previously described. Preferredheterocyclylalkyls contain a lower alkyl group. Non-limiting examples ofsuitable heterocyclylalkyl groups include piperidylmethyl,piperidylethyl, pyrrolidylmethyl, morpholinylpropyl, piperazinylethyl,azindylmethyl, azetidylethyl, oxiranylpropyl and the like. The bond toparent moiety is through the alkyl group.

“Hydroxyalkyl” means a HO-alkyl-group in which alkyl is as previouslydefined. Preferred hydroxyalkyls contain lower alkyl. Non-limitingexamples of suitable hydroxyalkyl groups include hydroxymethyl and2-hydroxyethyl.

“Acyl” means an organic acid group in which the —OH of the carboxylgroup is replaced by some other substituent. Suitable non-limitingexamples include H—C(O)—, alkyl-C(O)—, cycloalkyl-C(O)—,heterocyclyl-C(O)—, and heteroaryl-C(O)— groups in which the variousgroups are as previously described. The bond to the parent moiety isthrough the carbonyl. Preferred acyls contain a lower alkyl.Non-limiting examples of suitable acyl groups include formyl, acetyl andpropanoyl.

“Aroyl” means an aryl-C(O)— group in which the aryl group is aspreviously described. The bond to the parent moiety is through thecarbonyl. Non-limiting examples of suitable groups include benzoyl and1-naphthoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond tothe parent moiety is through the ether oxygen.

“Cycloalkoxy” means a cycloalkyl-O— group in which the cycloalkyl groupis as previously described.

“Cycloalkylalkoxy” means a cycloalkylalkyl-O group in which thecycloalkylalkyl group is as previously described.

“Aryloxy” means an aryl-O— group in which the aryl group is aspreviously described. Non-limiting examples of suitable aryloxy groupsinclude phenoxy and naphthoxy. The bond to the parent moiety is throughthe ether oxygen.

“Aralkyloxy” or “arylalkyloxy” means an aralkyl-O— group in which thearalkyl group is as previously described. Non-limiting examples ofsuitable aralkyloxy groups include benzyloxy and 1- or2-naphthalenemethoxy. The bond to the parent moiety is through the etheroxygen.

“Heteroarylalkoxy” means a heteroarylalkyl-O-group in which theheteroarylalkyl group is as previously described.

“Heterocycloalkylalkoxy” means a heterocycloalkylalkyl-O group in whichthe hetrocycloalkylalkyl group is as previously described.

“Akylthio” means an alkyl-S— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkylthio groupsinclude methylthio and ethylthio. The bond to the parent moiety isthrough the sulfur.

“Arylthio” means an aryl-S— group in which the aryl group is aspreviously described. Non-limiting examples of suitable arylthio groupsinclude phenylthio and naphthylthio. The bond to the parent moiety isthrough the sulfur.

“Aralkylthio” means an aralkyl-S— group in which the aralkyl group is aspreviously described. Non-limiting example of a suitable aralkylthiogroup is benzylthio. The bond to the parent moiety is through thesulfur.

“Heteroalkylthio” means a heteroalkyl-S— group in which the heteroalkylgroup is a previously described.

“Heteroarylthio” means a heteroaryl-S— group in which the heteroarylgroup is previously described.

“Alkoxycarbonyl” means an alkyl-O—CO— group. Non-limiting examples ofsuitable alkoxycarbonyl groups include methoxycarbonyl andethoxycarbonyl. The bond to the parent moiety is through the carbonyl.

“Aryloxycarbonyl” means an aryl-O—C(O)— group. Non-limiting examples ofsuitable aryloxycarbonyl groups include phenoxycarbonyl andnaphthoxycarbonyl. The bond to the parent moiety is through thecarbonyl.

“Aralkoxycarbonyl” means an aralkyl-O—C(O)— group. Non-limiting exampleof a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond tothe parent moiety is through the carbonyl.

“Alkylsulfonyl” means an alkyl-S(O₂)— group. Preferred groups are thosein which the alkyl group is lower alkyl. The bond to the parent moietyis through the sulfonyl.

“Arylsulfonyl” means an aryl-S(O₂)— group. The bond to the parent moietyis through the sulfonyl.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound’ or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

It is noted that carbons of formula I can be replaced with 1-3 siliconatoms, provided all valency requirements are satisfied.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

The straight line—as a bond generally indicates a mixture of, or eitherof, the possible isomers, non-limiting example(s) include, containing(R)- and (S)-stereochemistry. For example,

A dashed line

represents an optional bond.

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring atoms, non-limiting examples include carbon, nitrogenand sulfur ring atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples and Tables herein is assumed to have thehydrogen atom to satisfy the valences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any variable (e.g., aryl, heterocycle, R², etc.) occurs more thanone time in any constituent or formula, its definition on eachoccurrence is independent of its definition at every other occurrence.

Unless defined otherwise, all definitions for the variables follow theconvention that the group to the right forms the point of attachment tothe molecule; i.e., if a definition is arylalkyl, this means that thealkyl portion of the definition is attached to the molecule. Further,all divalent variable are attached from left to right.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

In this application, unless otherwise indicated, whenever there is astructural formula provided, such as those of Formula I, this formula isintended to encompass all forms of a compound such as, for example, anysolvates, hydrates, stereoisomers, tautomers, etc.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. The term “prodrug”, as employed herein, denotes acompound that is a drug precursor which, upon administration to asubject, undergoes chemical conversion by metabolic or chemicalprocesses to yield a compound of formula I or a salt and/or solvatethereof. A discussion of prodrugs is provided in T. Higuchi and V.Stella, Pro-drugs as Novel Delivery Systems (1987) Volume 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press, both of which are incorporated herein by referencethereto.

For example, if a compound of Formula I or a pharmaceutically acceptablesalt, hydrate or solvate of the compound contains a carboxylic acidfunctional group, a prodrug can comprise an ester formed by thereplacement of the hydrogen atom of the acid group with a group such as,for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula I contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C_(r) C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, —P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula I incorporates —NH— functional group, such asin a primary or secondary amine or in a nitrogen-containing heterocycle,such as imidazole or piperazine ring, a prodrug can be formed by thereplacement of a hydrogen atom in the amine group with a group such as,for example, R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ areeach independently (C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, orR-carbonyl is a natural α-aminoacyl or natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl, carboxy (C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N—(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N- or di-N,N—(C₁-C₆)alkylaminomorpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like.

One or more compounds of the invention may exist in unsolvated as wellas solvated forms with pharmaceutically acceptable solvents such aswater, ethanol, and the like, and it is intended that the inventionembrace both solvated and unsolvated forms. “Solvate” means a physicalassociation of a compound of this invention with one or more solventmolecules. This physical association involves varying degrees of ionicand covalent bonding, including hydrogen bonding. In certain instancesthe solvate will be capable of isolation, for example when one or moresolvent molecules are incorporated in the crystal lattice of thecrystalline solid. “Solvate” encompasses both solution-phase andisolatable solvates. Non-limiting examples of illustrative solvatesinclude ethanolates, methanolates, and the like. “Hydrate” is a solvatewherein the solvent molecule is H₂O.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTech., 5(1), article 12 (2004); and A. L. Bingham etal, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanambient temperature, and cooling the solution at a rate sufficient toform crystals which are then isolated by standard methods. Analyticaltechniques such as, for example I. R. spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

Metabolic conjugates, such as glucuronides and sulfates which canundergo reversible conversion to the compounds of Formula I arecontemplated in the present invention.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in producing the desired therapeutic, ameliorative, inhibitoryor preventative effect.

The terms “purified”, “in purified form” or “in isolated and purifiedform,” as used herein, for a compound refers to the physical state ofsaid compound after being isolated from a synthetic process (e.g. from areaction mixture), or natural source or combination thereof. Thus, theterm “purified”, “in purified form” or “in isolated and purified form”for a compound refers to the physical state of said compound after beingobtained from a purification process or processes described herein orwell known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell known to the skilled artisan.

“Capsule” is meant to describe a special container or enclosure made ofmethyl cellulose, polyvinyl alcohols, or denatured gelatins or starchfor holding or containing compositions comprising the activeingredients. Hard shell capsules are typically made of blends ofrelatively high gel strength bone and pork skin gelatins. The capsuleitself may contain small amounts of dyes, opaquing agents, plasticizersand preservatives.

“Tablet” is meant to describe a compressed or molded solid dosage formcontaining the active ingredients with suitable diluents. The tablet canbe prepared by compression of mixtures or granulations obtained by wetgranulation, dry granulation or by compaction.

“Oral gels” is meant to describe to the active ingredients dispersed orsolubilized in a hydrophillic semi-solid matrix.

“Powders for constitution” refers to powder blends containing the activeingredients and suitable diluents which can be suspended in water orjuices.

“Diluent” refers to substances that usually make up the major portion ofthe composition or dosage form. Suitable diluents include sugars such aslactose, sucrose, mannitol and sorbitol; starches derived from wheat,corn, rice and potato; and celluloses such as microcrystallinecellulose. The amount of diluent in the composition can range from about10 to about 90% by weight of the total composition, preferably fromabout 25 to about 75%, more preferably from about 30 to about 60% byweight, even more preferably from about 12 to about 60%.

“Disintegrants” refers to materials added to the composition to help itbreak apart (disintegrate) and release the medicaments. Suitabledisintegrants include starches; “cold water soluble” modified starchessuch as sodium carboxymethyl starch; natural and synthetic gums such aslocust bean, karaya, guar, tragacanth and agar; cellulose derivativessuch as methylcellulose and sodium carboxymethylcellulose;microcrystalline celluloses and cross-linked microcrystalline cellulosessuch as sodium croscarmellose; alginates such as alginic acid and sodiumalginate; clays such as bentonites; and effervescent mixtures. Theamount of disintegrant in the composition can range from about 2 toabout 15% by weight of the composition, more preferably from about 4 toabout 10% by weight.

“Binders” refers to substances that bind or “glue” powders together andmake them cohesive by forming granules, thus serving as the “adhesive”in the formulation. Binders add cohesive strength already available inthe diluent or bulking agent. Suitable binders include sugars such assucrose; starches derived from wheat, corn rice and potato; natural gumssuch as acacia, gelatin and tragacanth; derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate; cellulosicmaterials such as methylcellulose and sodium carboxymethylcellulose andhydroxypropylmethylcellulose; polyvinylpyrrolidone; and inorganics suchas magnesium aluminum silicate. The amount of binder in the compositioncan range from about 2 to about 20% by weight of the composition, morepreferably from about 3 to about 10% by weight, even more preferablyfrom about 3 to about 6% by weight.

“Lubricant” is meant to describe a substance added to the dosage form toenable the tablet, granules, etc. after it has been compressed, torelease from the mold or die by reducing friction or wear. Suitablelubricants include metallic stearates such as magnesium stearate,calcium stearate or potassium stearate; stearic acid; high melting pointwaxes; and water soluble lubricants such as sodium chloride, sodiumbenzoate, sodium acetate, sodium oleate, polyethylene glycols andd'l-leucine. Lubricants are usually added at the very last step beforecompression, since they must be present on the surfaces of the granulesand in between them and the parts of the tablet press. The amount oflubricant in the composition can range from about 0.2 to about 5% byweight of the composition, preferably from about 0.5 to about 2%, morepreferably from about 0.3 to about 1.5% by weight.

“Glidents” means materials that prevent caking and improve the flowcharacteristics of granulations, so that flow is smooth and uniform.Suitable glidents include silicon dioxide and talc. The amount ofglident in the composition can range from about 0.1% to about 5% byweight of the total composition, preferably from about 0.5 to about 2%by weight.

“Coloring agents” refers to excipients that provide coloration to thecomposition or the dosage form. Such excipients can include food gradedyes and food grade dyes adsorbed onto a suitable adsorbent such as clayor aluminum oxide. The amount of the coloring agent can vary from about0.1 to about 5% by weight of the composition, preferably from about 0.1to about 1%.

“Bioavailability” refers to the rate and extent to which the active drugingredient or therapeutic moiety is absorbed into the systemiccirculation from an administered dosage form as compared to a standardor control. Conventional methods for preparing tablets are known. Suchmethods include dry methods such as direct compression and compressionof granulation produced by compaction, or wet methods or other specialprocedures. Conventional methods for making other forms foradministration such as, for example, capsules, suppositories and thelike are also well known.

The compounds of Formula I can form salts which are also within thescope of this invention. Reference to a compound of Formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof Formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the Formula I may be formed, for example, by reacting a compound ofFormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates,) and the like. Additionally,acids which are generally considered suitable for the formation ofpharmaceutically useful salts from basic pharmaceutical compounds arediscussed, for example, by S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on its website). These disclosures areincorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamines, t-butyl amines, and saltswith amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g. decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g. benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons or sulfurs on various substituents, including enantiomeric forms(which may exist even in the absence of asymmetric carbons), rotamericforms, atropisomers, and diastereomeric forms, are contemplated withinthe scope of this invention. For example, if a compound of Formula Iincorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Individual stereoisomers of the compounds of the inventionmay, for example, be substantially free of other isomers, or may beadmixed, for example, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate” “prodrug” and the like, is intendedto equally apply to the salt, solvate and prodrug of enantiomers,stereoisomers, rotamers, tautomers, racemates or prodrugs of theinventive compounds.

Diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of Formula I may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of chiral HPLC column.

Polymorphic forms of the compounds of Formula I, and of the salts,solvates and prodrugs of the compounds of Formula I, are intended to beincluded in the present invention

The present invention also embraces isotopically-labelled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. Examples of isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, fluorine and chlorine and iodine, such as²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl and ¹²³I,respectively.

Certain isotopically-labelled compounds of Formula (I) (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Certain isotopically-labelled compounds of Formula (I)can be useful for medical imaging purposes. E.g., those labeled withpositron-emitting isotopes like ¹¹C or ¹⁸F can be useful for applicationin Positron Emission Tomography (PET) and those labeled with gamma rayemitting isotopes like ¹²³I can be useful for application in Singlephoton emission computed tomography (SPECT). Further, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and hencemay be preferred in some circumstances. Further, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements) and hencemay be preferred in some circumstances. Additionally, isotopicsubstitution at a site where epimerization occurs may slow or reduce theepimerization process and thereby retain the more active or efficaciousform of the compound for a longer period of time. Isotopically labeledcompounds of Formula (I), in particular those containing isotopes withlonger half lives (T½>1 day), can generally be prepared by followingprocedures analogous to those disclosed in the Schemes and/or in theExamples herein below, by substituting an appropriate isotopicallylabeled reagent for a non-isotopically labeled reagent.

Certain isotopically-labelled compounds of Formula I (e.g., thoselabeled with ³H and ¹⁴C) are useful in compound and/or substrate tissuedistribution assays. Tritiated (i.e., ³H) and carbon-14 (i.e., ¹⁴C)isotopes are particularly preferred for their ease of preparation anddetectability. Further, substitution with heavier isotopes such asdeuterium (i.e., ²H) may afford certain therapeutic advantages resultingfrom greater metabolic stability (e.g., increased in vivo half-life orreduced dosage requirements) and hence may be preferred in somecircumstances. Isotopically labelled compounds of Formula I cangenerally be prepared by following procedures analogous to thosedisclosed in the Schemes and/or in the Examples hereinbelow, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

The compounds according to the invention have pharmacologicalproperties; in particular, the compounds of Formula I can be useful asGPR 40 receptor agonists.

A preferred dosage is about 0.1 to 100 mg/kg of body weight/day of thecompound of Formula I. An especially preferred dosage is about 0.1 to 30mg/kg of body weight/day of a compound of Formula I, or apharmaceutically acceptable salt or solvate of said compound.

The pharmacological properties of the compounds of this invention may beconfirmed by a number of pharmacological assays. The exemplifiedpharmacological assays which are described later have been carried outwith the compounds according to the invention and their salts.

This invention is also directed to pharmaceutical compositions whichcomprise at least one compound of Formula I or a pharmaceuticallyacceptable salt or solvate of said compound and at least onepharmaceutically acceptable carrier.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.,magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18^(th) Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions or suspensions for intranasal administration.

An aspect of this invention is that the pharmaceutical composition is ina solid dosage form comprising a compound of Formula I or apharmaceutical acceptable salt, ester, solvate or prodrug thereof and aleast one pharmaceutically acceptable carrier, adjuvant or vehicle.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions or suspensions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations that are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

The compounds of this invention may also be delivered subcutaneously.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 1000 mg, preferably fromabout 1 mg to about 500 mg, more preferably from about 1 mg to about 100mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 1000 mg/day, preferably from 1 mg/day to 100 mg/day, inone to four divided doses, or in a sustained release form.

Compounds of Formula I (including their pharmaceutically acceptablesalts, esters, solvates and prodrugs) may be used in combination withother drugs that may also be useful in the treatment of amelioration ofthe diseases or conditions for which compounds of Formula I are useful.Such other drugs may be administered, by a route and in an amountcommonly used therefor, contemporaneously or sequentially with acompound of Formula I. In the treatment of patients who have Type 2diabetes, insulin resistance, obesity, lipid disorders, metabolicsyndrome, and co-morbidities that accompany these diseases, more thanone drug is commonly administered. The compounds of this invention maygenerally be administered to a patient who is already taking one or moreother drugs for these conditions.

When a compound of Formula I (including their pharmaceuticallyacceptable salts, esters, solvates and prodrugs) is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition in unit dosage form containing such other drugs and thecompounds of Formula I is preferred. However, the combination therapyalso includes therapies in which the compound of Formula I and one ormore other drugs are administered on different overlapping schedules. Itis also contemplated that when used in combination with one or moreother active ingredients, the compound of the present invention and theother active ingredients may be used in lower doses than when each isused singly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of Formula I.

Examples of other active ingredients that may be administered incombination with a compound Formula I, and either administeredseparately or in the same pharmaceutical composition, include, but arenot limited to:

(a) PPAR gamma agonists and selective PPAR gamma partial agonists(SPPARM's) including both glitazones and non-glitazones (e.g.troglitazone, pioglitazone, englitazone, MCC-555, rosiglitazone,balaglitazone, netoglitazone, T-131, LY-300512, and LY-818, and SPPARM'sdescribed in U.S. Pat. No. 6,525,083, WO 2004/020409, and WO2004/020408);

(b) biguanides such as metformin and phenformin;

(c) protein tyrosine phosphatase-1B (PTP-1B) inhibitors;

(d) dipeptidyl peptidase IV (DP-IV) inhibitors, such as sitagliptin,saxagliptin, and vildagliptin;

(e) insulin or insulin mimetics;

(f) sulfonylureas such as tolbutamide, glimepiride, glipizide, andrelated materials;

(g) α-glucosidase inhibitors (such as acarbose);

(h) agents which improve a patient's lipid profile, such as (i) HMG-CoAreductase inhibitors (lovastatin, simvastatin, rosuvastatin,pravastatin, fluvastatin, atorvastatin, rivastatin, itavastatin, ZD-4522and other statins), (ii) bile acid sequestrants (cholestyramine,colestipol, and dialkylaminoalkyl derivatives of a cross-linkeddextran), (iii) niacin receptor agonists, nicotinyl alcohol, nicotinicacid, or a salt thereof, (iv) PPARα agonists such as fenofibric acidderivatives (gemfibrozil, clofibrate, fenofibrate and bezafibrate), (v)cholesterol absorption inhibitors, such as for example ezetimibe, (vi)acy CoA:cholesterol acyltransferase (ACAT) inhibitors, such asavasimibe, (vii) CETP inhibitors, such as torcetrapib and compoundsdescribed in WO 2005/100298, WO 2006/014413, and WO 2006/014357, and(viii) phenolic anti-oxidants, such as probucol;

(i) PPAR α/γ dual agonists, such as muraglitazar, tesaglitazar,farglitazar, and JT-501;

(j) PPARδ agonists such as those disclosed in WO 97/28149;

(k) antiobesity compounds such as fenfluramine, dexfenfluramine,phentiramine, subitramine, orlistat, neuropeptide Y5 inhibitors, Mc4ragonists, cannabinoid receptor 1 (CB-1) antagonists/inverse agonists,and β₃ adrenergic receptor agonists;

(l) ileal bile acid transporter inhibitors;

(m) agents intended for use in inflammatory conditions such as aspirin,non-steroidal anti-inflammatory drugs, glucocorticoids, azulfidine, andcyclo-oxygenase 2 selective inhibitors;

(n) glucagon receptor antagonists;

(o) GLP-1,

(p)GIP-1,

(q) GLP-1 analogs, such as exendins, for example exenatide (Byetta),

(r) Glucokinase activators;

(s) GPR 119 agonists;

(t) GPR120 agonists; and

(u) Hydroxysterol dehydrogenase-1 (HSD-1) inhibitors.

The above combinations include combinations of a compound of the presentinvention not only with one other active compounds, but also with two ormore other active compounds. Non-limiting examples include combinationsof compounds having Formula I with two or more active compounds selectedfrom biguanides, sulfonylureas, HMG-CoA reductase inhibitors, other PPARagonists, PTP-1B inhibitors, DP-IV inhibitors, and anti-obesitycompounds.

Another aspect of this invention is a kit comprising a therapeuticallyeffective amount of at least one compound of Formula I or apharmaceutically acceptable salt or solvate of said compound and apharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of atleast one compound of Formula I, or a pharmaceutically acceptable saltor solvate of said compound and an amount of at least one therapeuticagent listed above, wherein the amounts of the two or more ingredientsresult in desired therapeutic effect.

In general, the compounds in the invention may be produced by a varietyof processes know to those skilled in the art and by know processesanalogous thereto. The invention disclosed herein is exemplified by thefollowing preparations and examples which should not be construed tolimit the scope of the disclosure. Alternative mechanistic pathways andanalogous structures will be apparent to those skilled in the art. Thepractitioner is not limited to these methods.

One skilled in the art will recognize that one route will be optimizeddepending on the choice of appendage substituents. Additionally, oneskilled in the art will recognize that in some cases the order of stepshas to be controlled to avoid functional group incompatability.

The prepared compounds may be analyzed for their composition and purityas well as characterized by standard analytical techniques such as, forexample, elemental anyalysis, NMR, mass spectroscopy and IR spectra.

One skilled in the art will recognize that reagents and solventsactually used may be selected from several reagents and solvents wellknown in the art to be effective equivalents. Hence, when a specificsolvent or reagent is mentioned, it is meant to be an illustrativeexample of the conditions desirable for that particular reaction schemeand in the preparations and examples described below.

Where NMR data are presented, ¹H spectra were obtained on either aVarian VXR-200 (200 MHz, ¹H), Varian Gemini-300 (300 MHz), VarianMercury VX-400 (400 MHz), or Bruker-Biospin AV-500 (500 MHz), and arereported as ppm with number of protons and multiplicities indicatedparenthetically. Where LC/MS data are presented, analyses was performedusing an Applied Biosystems API-100 mass spectrometer and C18 column,10-95% CH₃CN—H₂O (with 0.05% TFA) gradient. The observed parent ion isgiven.

The invention disclosed herein is exemplified by the followingillustrative processes which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

The invention disclosed herein is exemplified by the followingillustrative processes which should not be construed to limit the scopeof the disclosure. Alternative mechanistic pathways and analogousstructures will be apparent to those skilled in the art.

Method A

Method A describes general methods towards the preparation of compoundsof formula (I) that relies on the formation of ketone intermediate A6.One way to prepare intermediate A6 is via coupling phenol ketoneintermediate A1 with A2 (where LG is a leaving group such as halo ortriflate and G is aryl or heteroaryl) under SNAr conditions using a basesuch as cesium carbonate. Another way to prepare A6 is to coupleintermediate A1 with alcohol A3 (where G is arylalkyl orheteroarylalkyl) under Mitsunobu conditions such as withtriphenylphosphine and diisopropyl azodicarboxylate. An alternate way togenerate A6 is to couple activated arylketone A4 (where LG is a leavinggroup such as halo or triflate) with alcohol or phenol-like A5 underSNAr conditions in the presence of a base such as cesium carbonate. A4can be generated from A1 when desirable, via condensation with triflicanhydride for LG=triflate, or via halogenation with triphenylphosphineand bromine for LG=bromine.

Method B

Method B describes one general method to convert intermediate A6 into acompound of formula (I). Ketone intermediate A6 is reacted with2,4-thiazolidine dione B1 in the presence of a base such as sodiumacetate to produce intermediate B2. A2 is then reduced with a reducingagent such as lithium borohydride to give the compound of formula (I) asa mixture of diastereoisomers. Those diastereoisomers can be optionallyseparated via chiral purification, resolution or via any method known toone skilled in the art. A2 may also be reduced under asymmetricreduction conditions to generate the compound of formula (I) as anoptically enriched compound.

Method C

Method C is a general alternate method for compounds of formula (I) thatrelies on the formation of intermediate C8. Intermediate A3 is firstprotected at the phenol into intermediate A3a by using standard phenolprotection methodology such as reaction with iodomethane when PG=methyl.Intermediate A3-p is then subjected to Reformatsky conditions, such aszinc and ethyl bromoacetate C1 or an equivalent, to provide C2.Intermediate C2 is reduced, optionally under asymmetric reductionconditions, to generate intermediate C3 as an optically enrichedcompound or as a mixture of diastereoisomers that can be optionallypurified via chiral purification, resolution or via any method known toone skilled in the art. C3 is bromated under general brominationconditions such as treatment with N-bromosuccinimide and a base such asLHMDS to provide intermediate C4. The 2,4-thiazolidine dione ring isthen installed through treatment of C4 with thiourea C5 (producing C6)followed by hydrolysis to give C7. Removal of the protection group inC7, for example with boron tribromide when PG=methyl, results inintermediate C8. Partial variation around Method C may also be apparentto those skilled in the art, for example by using an alternateintermediate C3 such as:

Method D

Method D is a general alternate method for the preparation ofintermediate C7 that uses conditions similar to the ones described byFalck, J. R. et al. Bioorg. Med. Chem. Lett. 2008, 18, 1768.Intermediate C3 is hydrolyzed in the presence of a base such as lithiumhydroxide to generate acid D1 which can be optionally optically enrichedvia chiral purification, resolution (for example with a chiral salt orchiral amine) or via any method known to one skilled in the art. D1 isthen converted into an acyl chloride with a reagent such as oxalylchloride and then reacted with 2-oxazolidinone D2 to give intermediateD3. D3 is in turn converted into thiocyanato intermediate D5 via theformation of an enol boronate with di-n-butylboron triflate anddiisopropylamine for example, followed by treatment withN-thiocyanatosuccinimide D4. The 2,4-thiazolidine dione ring is theninstalled via treatment of D5 with a base such as sodium methoxidefollowed by hydrolysis to give C7. Alternate strategies using a chiraloxazolidinone instead of D2 to allow for the separation of D1enantiomers as in WO 2006/083612 may be envioned for those skilled inthe art. Such strategies may generate optically enriched or opticallypure C7 following the sodium methoxide and hydrolysis treatment.Variation of Method D may also be apparent to those skilled in the art,for example by using an alternate intermediate C3 such as:

Method E

Method E is a general alternate method that utilizes processes describedin Methods A, C and D. Following the deprotection of the protectinggroup in intermediate C3, for example with boron tribromide forPG=methyl, the resulting phenol E1 is converted into intermediate E2using any of the processes described in Method A, then E2 is reactedusing steps C3 to C7 of Method C, or the steps in method D, to give thecompound of formula (I) as an optically enriched compound or as amixture of diastereoisomers that can be optionally separated via chiralpurification, resolution or via any method known to one skilled in theart. Variation of Method E may also be apparent to those skilled in theart, for example by using an alternate intermediate C3 such as:

Method F

Method F is a general alternate method that utilizes any of theprocesses described in Method A, as well as alternate conditions knownto one skilled in the art, to convert intermediate C8 into the compoundof formula (I) as an optically enriched compound or as a mixture ofdiastereoisomers that can be optionally separated via chiralpurification, resolution or via any method known to one skilled in theart. Variation of Method F may also be apparent to those skilled in theart, for example by using an alternate intermediate C8 such as:

Method G

Method G is a general alternate method for the introduction of2,4-oxadiazolidine dione instead of the 2,4-thiodiazolidine dione thatutilizes alpha-hydroxylation of the intermediate C3 using conditionssimilar to the ones described by Rubottom, G. M. et al. Synth. Commun.1981, 11, 505. In this method, C3 is treated with a base such as NaHMDSfollowed by trimethylsilyl chloride and the resulting ketene acetalintermediate is trapped with MCPBA followed by treatment with TBAF togive G1. G1 is reacted with ammonia to yield the hydroxyamide G2. G2 isin turn converted into 2,4-oxazolidine dione G4 through treatment withdimethylcarbonate G3. Following the deprotection of the protecting groupin G4, for example with boron tribromide for PG=methyl, the resultingphenol G5 undergoes any of the processes described in Method A, as wellas alternate conditions known to one skilled in the art, to give thecompound of formula (I) as an optically enriched compound or as amixture of diastereoisomers that can be optionally separated via chiralpurification, resolution or via any method known to one skilled in theart. Variation of Method G may also be apparent to those skilled in theart, for example by using an alternate intermediate C3 such as:

Method H

Method H is a modification of method G to install alpha hydroxyl acidsin lieu of the 2,4-thiodiazolidine dione. The protecting group in G1 isremoved, for example with boron tribromide for PG=methyl, and theresulting phenol H1 is reacted following any of the processes describedin Method A, as well as condition alternatives known to one skilled inthe art, to give H2. H2 is then hydrolyzed with lithium hydroxide togive the compound of formula (I) as an optically enriched compound or asa mixture of diastereoisomers that can be optionally separated viachiral purification, resolution or via any method known to one skilledin the art. As an alternate variation, the alpha-hydroxyl group in G1may be protected with tert-butylchlorodiphenylsilane prior to thesequence of steps described in Method H scheme. After hydrolysis withlithium hydroxide, the resulting alpha-O-protected acid may then betreated with TBAF to generate the compound of formula (I). Variation ofMethod H may also be apparent to those skilled in the art, for exampleby using an alternate intermediate G1 such as:

Example 1

Example 1, Step 1

To a solution of ethyl 3-oxocyclobutanecarboxylate 1-1 (4.51 g, 31.7mmol) in anhydrous diethyl ether (300 mL) at −78° C. under N₂ was addeddropwise (3-methoxyphenyl)magnesium bromide 1-2 (1 N in THF, 32.0 mL,32.0 mmol) over 70 min. After complete addition, the cold bath wasremoved, and the reaction mixture was warmed to room temperature. After30 min, aqueous saturated sodium sulfate (250 mL) was added. The twolayers were separated, and the aqueous layer was extracted with diethylether. The combined organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (eluting with EtOAc/hexanes 0:100 to 30:70) to provide1-3 (4.31 g, 54%) as a colorless oil. ¹H NMR (500 MHz, CDCl₃) δ7.28 (t,J=7.9 Hz, 1H), 7.08-7.05 (m, 2H), 6.84 (ddd, J=8.2, 2.6, 0.8 Hz, 1H),4.20 (q, J=7.1 Hz, 2H), 3.83 (s, 3H), 3.02 (s, 1H), 2.89-2.84 (m, 3H),2.63-2.59 (m, 2H), 1.28 (t, J=7.1 Hz, 3H).

Example 1, Step 2

To a solution of 1-3 (4.30 g, 17.2 mmol) in ethanol (86 mL) was added10% Pd/C (1.82 g). The mixture was stirred under hydrogen atmosphere (20psi) for 4 days. The mixture was filtered through celite, and the filtercake was rinsed with hexanes (50 mL). The filtrate was concentrated invacuo, and the residue was purified by silica gel chromatography(eluting with EtOAc/hexanes 0:100 to 15:85), to provide 1-4 (3.07 g,76%) as a colorless liquid. ¹H NMR (500 MHz, CDCl₃) δ7.22 (t, J=7.8 Hz,1H), 6.83 (dd, J=7.6, 0.8 Hz, 1H), 6.77 (t, J=2.1 Hz, 1H), 6.75 (dd,J=8.1, 2.5 Hz, 1H), 4.15 (q, J=7.1 Hz, 2H), 3.80 (s, 3H), 3.45-3.40 (m,1H), 3.12-3.04 (m, 1H), 2.62-2.56 (m, 2H), 2.44-2.36 (m, 2H), 1.26 (t,J=7.1 Hz, 3H).

Example 1, Step 3

To a solution of 1-4 (3.04 g, 13.0 mmol) in 70% ethanol (65 mL) wasadded KOH (85%, 7.28 g, 110 mmol). The solution was heated at 95° C. for3 h, concentrated to 20 mL, and acidified to pH 1-2 with 1 Nhydrochloric acid. The mixture was extracted with chloroform. Theorganic layer was dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography (elutingwith EtOAc/hexanes 0:100 to 40:60), to provide 1-5 (2.47 g, 92%) as acolorless oil. NMR (500 MHz, CDCl₃) δ 7.23 (t, J=7.8 Hz, 1H), 6.84 (d,J=7.5 Hz, 1H), 6.78 (s, 1H), 6.75 (dd, J=8.1, 2.4 Hz, 1H), 3.80 (s, 3H),3.49-3.43 (m, 1H), 3.18-3.11 (m, 1H), 2.66-2.61 (m, 2H), 2.48-2.41 (m,2H).

Example 1, Step 4

A mixture of 1-5 (2.47 g, 12.0 mmol) and polyphosphoric acid (4.80 g,48.0 mmol) under N₂ was heated at 90° C. for 1.5 h. Water (50 mL) wasadded, and the mixture stirred with a spatula until all the deep redmaterial changed to a slightly yellow mixture. The aqueous mixture wasextracted with diethyl ether. The organic extract was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (eluting with EtOAc/hexanes 0:100 to 10:90), toprovide 1-6 (1.27 g, 56%) as a yellow oil. ¹H NMR (500 MHz, CDCl₃) δ7.94 (d, J=8.5 Hz, 1H), 6.83 (dd, J=8.5, 2.4 Hz, 1H), 6.72 (d, J=2.4 Hz,1H), 3.86 (s, 3H), 3.27 (q, J=4.6 Hz, 1H), 3.15 (q, J=5.8 Hz, 1H),2.93-2.88 (m, 2H), 2.34-2.31 (m, 2H).

Example 1, Step 5

A mixture of 1-6 (1.27 g, 6.75 mmol), zinc dust (1.58 g, 24.3 mmol),copper(I) chloride (66 mg, 0.68 mmol) and I₂ (1 crystal) in THF (29 mL)was heated at 65° C. under N₂ for 15 min. Ethyl bromoacetate (3.38 g,20.2 mmol) was added dropwise over 5 min. The mixture was heated at 65°C. overnight. The oil bath temperature was increased to 70° C., andadditional zinc dust (1.58 g, 24.3 mmol) and copper(I) chloride (66 mg,0.68 mmol) were added. After 10 min, additional ethyl bromoacetate (3.38g, 20.2 mmol) was added dropwise. The reaction was heated at reflux for4 h, cooled to room temperature, and filtered through celite. The filtercake was washed with DCM (30 mL). The filtrate was concentrated invacuo, and the residue was dissolved in EtOAc (50 mL). The pH wasadjusted to ≈1 with hydrochloric acid (1 N), and the two layers wereseparated. The aqueous layer was extracted with EtOAc and the combinedorganic layers were dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography (elutingwith EtOAc/hexanes 0:100 to 5:95), to provide 1-7 (971 mg, 55%) as apale yellow oil. ¹H NMR (500 MHz, CDCl₃) δ 7.70 (d, J=8.7 Hz, 1H), 6.75(dd, J=7.6, 2.6 Hz, 1H), 6.63 (d, J=2.6 Hz, 1H), 6.25 (s, 1H), 4.88 (q,J=6.0 Hz, 1H), 4.19 (q, J=6.8 Hz, 2H), 3.82 (s, 3H), 3.15 (q, J=5.4 Hz,1H), 2.69-2.65 (m, 2H), 1.86-1.84 (m, 2H), 1.31 (t, J=7.0 Hz, 3H).

Example 1, Step 6

A mixture of 1-7 (500 mg, 1.94 mmol) and 10% Pd/C (205 mg, 0.194 mmol)in ethanol (19 mL) was stirred under hydrogen atmosphere (30 psi) for 4days. The mixture was filtered through celite. The filter cake waswashed with DCM (30 mL). The filtrate was concentrated to give 1-8 (506mg, 100%) as a yellow liquid, which was used in the next step withoutfurther purification. ¹H NMR (500 MHz, CDCl₃) δ7.13 (d, J=8.4 Hz, 1H),6.71 (dd, J=8.3, 2.7 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H), 4.19 (q, J=7.1 Hz,2H), 3.77 (s, 3H), 3.57-3.55 (m, 1H), 3.04 (q, J=4.6 Hz, 1H), 2.80 (dd,J=15.4, 4.4 Hz, 1H), 2.64-2.63 (m, 1H), 2.49-2.43 (m, 2H), 2.28-2.25 (m,1H), 1.51-1.49 (m, 2H), 1.28 (t, J=7.1 Hz, 3H).

Example 1, Step 7

To a solution of 1-8 (300 mg, 1.15 mmol) in ethanol (11 mL) was addedlithium hydroxide monohydrate (386 mg, 9.2 mmol) and water (1 mL). Themixture was heated at 50° C. for 3 h. The solvent was evaporated invacuo, and the residue was diluted with chloroform (20 mL) and acidifiedwith hydrochloric acid (1 N) to pH≈1 at 0° C. The two layers wereseparated, and the aqueous layer was extracted with chloroform. Thecombined organic extract was dried over Na₂SO₄, filtered, andconcentrated. The residue was purified by silica gel chromatography(eluting with EtOAc/hexanes 0:100 to 40:60), to provide 1-9 (264 mg,98%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.16 (d, J=8.3 Hz, 1H),6.73 (dd, J=8.3, 2.6 Hz, 1H), 6.57 (d, J=2.6 Hz, 1H), 3.78 (s, 3H),3.59-3.57 (m, 1H), 3.05 (q, J=5.4 Hz, 1H), 2.88 (dd, J=15.8, 4.2 Hz,1H), 2.72-2.70 (m, 1H), 2.54 (dd, J=15.9, 10.2 Hz, 1H), 2.49-2.45 (m,1H), 2.31-2.27 (m, 1H), 1.54-1.48 (m, 2H).

Example 1, Step 8

Oxalyl chloride (30 μL, 0.36 mmol) was added dropwise to a solution of1-9 (70 mg, 0.30 mmol) and DMF (1 drop) in DCM (0.6 mL) at 0° C. underN₂. The mixture was stirred at room temperature for 1 h and concentratedto ≈0.2 mL to give crude 1-10. In a separate flask containing2-oxazolidinone (47 mg, 0.54 mmol) was added anhydrous THF (1 mL). Theflask was cooled to −42° C. and sodium bis(trimethylsilyl)amide (1 M inTHF, 0.60 mL, 0.60 mmol) was added dropwise. The cold bath was removed,and the yellow mixture was stirred for 10 min. The mixture was thencooled to −42° C. A solution of crude 1-10 in THF (0.7 mL) was addeddropwise. The reaction was stirred at −42° C. for 30 min, warmed to roomtemperature, and stirred for 3 h. The reaction was diluted withsaturated aqueous ammonium chloride (15 mL) at 0° C. and extracted withEtOAc. The organic extract was dried over Na₂SO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (eluting with EtOAc/hexanes 0:100 to 30:70) to provide1-11 (82 mg, 90%) as a white solid. ¹H NMR (500 MHz, CDCl₃) δ 7.25 (d,J=8.8 Hz, 1H), 6.72 (dd, J=8.3, 2.7 Hz, 1H), 6.56 (d, J=2.6 Hz, 1H),4.43 (t, J=7.8 Hz, 2H), 4.06 (t, J=7.9 Hz, 2H), 3.77 (s, 3H), 3.66 (td,J=10.0, 3.0 Hz, 1H), 3.48 (dd, J=16.2, 3.5 Hz, 1H), 3.14-3.01 (m, 2H),2.67-2.60 (m, 1H), 2.47-2.41 (m, 1H), 2.30-2.24 (m, 1H), 1.59-1.47 (m,2H).

Example 1, Step 9

N-thiocyanatosuccinimide reagent 1-12 was prepared according to Toste,F. et al Synth. Commun. 1995, 25, 1277. Di-n-butylboron triflate (1 M inDCM, 0.26 mL, 0.26 mmol) was added dropwise to a solution of 1-11 (72mg, 0.24 mmol) in anhydrous DCM (1.8 mL) under N₂ at 0° C.Diisopropylethylamine (48 μL, 0.28 mmol) was added dropwise. Theslightly yellow mixture was stirred at 0° C. for 1 h, and then cooled to−78° C. A solution of 1-12 (90 mg, -0.50 mmol) in DCM (1 mL) was addeddropwise. The mixture was stirred at −78° C. for 2 h, warmed to roomtemperature, and then quenched with pH 7 buffer [3 mL, prepared bydissolving NaH₂PO₄ (1.20 g) and Na₂HPO₄ dodecahydrate (2.23 g) in water(50 mL)] and aqueous H₂O₂ (35%, 0.2 mL). The mixture was stirred for 30min and extracted with EtOAc. The organic extract was dried over Na₂SO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (eluting with EtOAc/hexanes 0:100 to 50:50) toprovide a mixture (73 mg) of 1-11 and 1-13, which was further purifiedby prep-HPLC(XBridge ODB C18 5 μm, 30×150 mm, 43 mL/min,acetonitrile/water 10:90 to 90:10) to provide 1-11 (34 mg, 47%) and 1-13(27 mg, 31%, dr 7:3) as a white solid. 1-13: ¹H NMR (500 MHz, CDCl₃) δ7.54 (d, J=8.3 Hz, 0.3H), 7.04 (d, J=8.4 Hz, 0.7H), 6.75 (dd, J=8.5, 2.8Hz, 0.3H), 6.63 (dd, J=8.4, 2.7 Hz, 0.7H), 6.60 (s, 0.7H), 6.59 (s,0.3H), 5.48 (d, J=7.8 Hz, 0.3H), 5.42 (d, J=9.4 Hz, 0.7H), 4.52-4.40 (m,2H), 4.25-4.08 (m, 2H), 3.93 (dd, J=9.3, 3.0 Hz, 0.7H), 3.81-3.79 (m,0.3H), 3.79 (s, 0.9H), 3.77 (s, 2.1H), 3.15-3.12 (m, 0.7H), 3.08-3.04(m, 1H), 2.80-2.77 (m, 0.3H), 2.58 (td, J=9.1, 5.8 Hz, 0.7H), 2.50 (td,J=9.1, 6.0 Hz, 0.3H), 2.37 (td, J=9.7, 5.8 Hz, 0.7H), 2.29 (td, J=9.7,5.8 Hz, 0.3H), 1.72 (q, J=8.3 Hz, 1H), 1.50-1.46 (m, 1H).

Example 1, Step 10

Sodium methoxide (25% in methanol, 41 μL, 0.18 mmol) was added dropwiseto a solution of 1-13 (25 mg, 0.070 mmol) in methanol/THF (3.5 mL, 4:1,v/v) at 0° C. under N₂. The cold bath was removed, and the mixture wasstirred at room temperature for 1 h. Hydrochloric acid (2 N) was addeduntil the solution reached pH≈2. The mixture was stirred for 3 h,diluted with water (8 mL), and extracted with EtOAc (3×10 mL). Theorganic extract was dried over Na₂SO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography (elutingwith EtOAc/hexanes 0:100 to 40:60) to provide 1-14 (10 mg, 50%, dr 1:1)as a white semisolid. ¹H NMR (500 MHz, CDCl₃)

7.96 (br s, 0.5H), 7.92 (br s, 0.5H), 7.18 (d, J=8.4 Hz, 0.5H), 6.97 (d,J=8.4 Hz, 0.5H), 6.75 (dd, J=8.3, 2.7 Hz, 0.5H), 6.69 (dd, J=8.4, 2.7Hz, 0.5H), 6.61-6.60 (m, 1H), 5.15 (d, J=4.3 Hz, 0.5H), 4.57 (d, J=2.3Hz, 0.5H), 4.19 (br s, 0.5H), 4.06 (br s, 0.5H), 3.79 (s, 1.5H), 3.78(s, 1.5H), 3.05-3.01 (m, 1H), 2.82-2.80 (m, 0.5H), 2.73-2.69 (m, 0.5H),2.55-2.51 (m, 1H), 2.37-2.33 (m, 0.5H), 2.29-2.25 (m, 0.5H), 2.03 (t,J=8.8 Hz, 0.5H), 1.61-1.58 (m, 1.5H).

Example 1, Step 11

Boron tribromide (1 M in hexanes, 90 μL, 90 μmol) was added to asolution of 1-14 (8.8 mg, 30 μmol) in DCM (0.3 mL) at −78° C. under N₂.The cold bath was removed, and the orange mixture was stirred at roomtemperature for 1 h. Methanol (0.5 mL) was added, and the mixturestirred for 5 min. The mixture was concentrated in vacuo, and theresidue was dried under high vacuum for 1 h to give 1-15 (10 mg, >99%)as a slightly brown solid, which was used in the next step withoutfurther purification.

Example 1, Step 12

2-Chloro-1-fluoro-4-(trifluoromethyl)benzene 1-16 (7.0 mg, 36 μmol),1-15 (10 mg, ≈30 μmol), cesium carbonate (29 mg, 90 μmol), andN,N-dimethylacetamide (0.3 mL) were added to a pressure tube and flushedwith N₂. The tube was quickly sealed, and placed in a pre-heated oilbath (120° C.). The mixture was stirred for 30 min, cooled to roomtemperature, and acidified with hydrochloric acid (1 N) to pH≈1. Themixture was extracted with EtOAc. The organic extract was dried overNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (eluting with EtOAc/hexanes 0:100 to 30:70) toprovide Example 1 (9 mg, 67%, dr 1:1) as a pale yellow solid. ¹H NMR(500 MHz, CDCl₃)

7.91 (s, 1H), 7.73 (dd, J=5.6, 1.8 Hz, 1H), 7.46-7.45 (m, 1H), 7.29-7.28(m, 0.5H), 7.06-7.03 (m, 0.5H), 7.01 (d, J=9.2 Hz, 1H), 6.88 (dd, J=8.2,2.5 Hz, 0.5H), 6.82 (dd, J=8.3, 2.5 Hz, 0.5H), 6.73-6.72 (m, 1H), 5.15(d, J=4.2 Hz, 0.5H), 4.60 (d, J=2.2 Hz, 0.5H), 4.24 (s, 0.5H), 4.11 (s,0.5H), 3.06-3.03 (m, 1H), 2.86-2.84 (m, 0.5H), 2.75-2.74 (m, 0.5H),2.58-2.53 (m, 1H), 2.41-2.36 (m, 0.5H), 2.31-2.29 (m, 0.5H), 2.05-2.02(m, 0.5H), 1.64-1.61 (m, 1.5H). MS (ESI) m/z 452.2 [M-H]⁻. MP: 77-80° C.HPLC >99%, t_(R)=26.3 & 26.5 min.

The compounds in Table 1 were prepared following procedures similar tothose of Example 1, including using intermediates described in UK Pat.Appl. (1994), GB 2276379 and separing the enantiomers of intermediate1-8 via chiral preparative HPLC.

TABLE 1 Mass Spec (M − H)⁻; retention Example No. COMPOUND time (min)1-A

510.3; 27.1 & 27.3 1-B

452.2; 26.2 & 26.4 1-C

510.3; 26.9 & 27.1 1-D

409.4; 22.6 1-E

470.6; 22.8 1-F

427.1; 20.4 & 20.6

Example 2

Example 2, Step 1

Intermediate 1-8 from Example 1 was separated by chiral preparative HPLCto give enantiomer 1-8A. This enantiomer was treated with sodiumhexamethyldisylazide in THF at −78° C. followed by addition of chlorotrimethylsilane and warming to room temperature to give an intermediateenol silane. This enol silane was treated with meta-chloroperoxybenzoicacid from −7° C. to room temperature followed by treatment with TBAF toprovide compound 2-1 after workup and purification by silica gelchromatography.

Example 2, Step 2

Compound 2-1 was reacted with 7N ammonia in methanol at room temperaturefor 2 days to provide compound 2-2 after purification by silica gelchromatography.

Example 2, Step 3

Compound 2-1 was reacted with ethyl carbonate and sodium methoxide inanhydrous ethanol at 95° C. to provide compound 2-3 after workup andpurification by silica gel chromatography.

Example 2, Step 4

Compound 2-3 was subjected to conditions described in Example 1, steps11 and 12 to provide Example 2 after workup and purification by silicagel chromatography. ¹H NMR (500 MHz, CDCl₃) δ 7.74 (m, 1H), 7.60 (s,1H), 7.46-7.45 (m, 1H), 7.36-7.35 (m, 0.5H), 7.28-7.26 (m, 1H),7.03-7.00 (m, 1H), 6.91-6.89 (m, 0.5H), 6.83-6.82 (m, 0.5H), 6.74-6.73(m, 1H), 5.47 (br s, 0.5H), 5.04 (br s, 0.5H), 3.79 (s, 0.5H), 3.77 (s,0.5H), 3.08-3.05 (m, 1H), 3.02-2.99 (m, 0.5H), 2.74-2.72 (m, 0.5H),2.60-2.58 (m, 1H), 2.39-2.35 (m, 1H), 1.88-1.84 (m, 1H), 1.60-1.55 (m,1H). MS (ESI) m/z: 436.4 [M-H]⁻. HPLC >99%, t_(R)=24.8.

Example 3

Example 3, Step 1

Methyl 3-chlorocyclobutane carboxylate 3-1 is coupled with3-methoxyphenol following conditions similar to the ones described in US2004/026482 to provide compound 3-2 as a cis and trans mixture, afterworkup and purification.

Example 3, Step 2

Compound 3-2 is hydrolyzed with sodium hydroxide in aqueous isopropanolfollowed by neutralization with aqueous HCl and extraction to givecompound 3-3 as a cis and trans mixture, after purification.

Example 3, Step 3

Treatment of 3-3 with aluminum chloride in DCE, or an alternative methodsuch as trifluoroacetic anhydride followed by acidic aqueous treatment,yields compound 3-4 after workup and purification in addition tounreacted trans reagent.

Example 3, Step 4

Compound 2-4 is converted into compound 2-5 following conditions similarto the ones described in Example 1, Steps 5 to 11.

Example 3, Step 5

Reaction of compound 3-5 with 4-fluoronaphthonitrile 3-6 and cesiumcarbonate in DMF affords Example 3 after workup and purification.

Example 4

Example 4, Step 1

2-Hydroxy-4-methoxybenzaldehyde 4-1 is reacted with methoxymethylchloride and triethylamine in DCM to provide compound 4-2 after workupand purification.

Example 4, Step 2

Compound 4-2 is reduced with sodium borohydride in methanol to givecompound 4-3 after workup and purification.

Example 4, Step 3

Reaction of 4-3 with triphenylphosphine and tetrabromomethane in DCMaffords compound 4-4 after workup and purification.

Example 4, Step 4

Compound 4-4 is treated with sodium cyanide in DMF to provide compound4-5 after workup and purification.

Example 4, Step 5

Compound 4-5 is treated with 1,3-dibromo-2,2-dimethoxypropane 4-6following conditions similar to the one described by Shao, P. P et al.Tet. Lett. 2008, 49, 3554 to give compound 4-7 after workup andpurification.

Example 4, Step 6

Hydrolysis of compound 4-7 gives compound 4-8 after purification.

Example 4, Step 7

Compound 4-8 is reduced with sodium borohydride in methanol to providecompound 4-9 after workup and purification.

Example 4, Step 8

Reaction of 4-9 with triphenylphosphine and tetrabromomethane in DCMaffords compound 4-10 after workup and purification.

Example 4, Step 9

Treatment of 4-10 with a base such as NaH in a solvent such as DMFaffords compound 4-11 after workup and purification.

Example 4, Step 10

Compound 4-11 is hydrolysed under acidic conditions to an acid which isthen treated with oxalyl chloride in DCM with a drop of DMF to afford anacyl chloride intermediate. This acyl chloride intermediate is thentreated with diazomethane in DCM, optionally in the presence oftriethylamine, to give compound intermediate 4-12.

Example 4, Step 11

Arndt-Eistert rearrangement of 4-12 with silver oxide in water resultsin compound 4-13 after workup and purification.

Example 4, Step 12

Compound 4-13 is converted into compound 4-14 following conditionssimilar to the ones described in Example 1, Steps 8 to 11.

Example 4, Step 12

Reaction of compound 4-14 with 2,3-dichloro-5-(trifluoromethyl)pyridineand cesium carbonate in DMF affords Example 4 after workup andpurification.

GPR40 Primary FLIPR Assay:

The cDNA encoding the human GPR40 receptor was subcloned into thepcDNA3.1 expression vector and stably transfected into HEK 293 cellsusing Lipofectamine 2000. Cells stably expressing the hGPR40 receptorwere harvested and plated into poly-D-lysine coated 384 well plates at aconcentration 8,000 cells/well and incubated for approximately 24 hoursin a 37° C. incubator with 5% CO₂. On the day of the experiment, FLIPRBuffer A was prepared by combining 20 mM Hepes, 0.04% CHAPS and 2.5 mMprobenecid with Hanks Buffer. Molecular probes Calcium 4 Dye was thendiluted 1:20 into FLIPR buffer A using manufacturers instructions tomake the cell dye-loading buffer. Medium was removed from the cells,after which 35 μl of dye-loading buffer was added. The plates wereincubated at 37° C. in a 5% CO₂ incubator for 1 hour, after which thenwere left at room temperature for another hour. Plates were then placedin the FLIPR 384 and 5 μl of an 8× concentration of compound was addedby the FLIPR robotics.

Maximum fluorescence response at each concentration of compound wasdetermined by the FLIPR384 software. Maximum Fluorescence for eachconcentration was then compared with the response seen in the absence ofcompound (% control), and the EC₅₀ for an increase in baselinefluorescence in the presence of compound was calculated using MicrosoftExcel Fit software. The maximum fluorescent response of the compound wasalso compared to that seen in the presence of a 30 uM concentration of astandard compound and a percent maximum response was calculated. Datawere reported for both EC₅₀ and % Maximum response.

The compounds had an EC₅₀ higher than 20 nM and less than 1 μM. Thecompound has a maximum response higher than 50%.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications, and variations areintended to fall within the spirit and scope of the present invention.

1. A compound of the formula:G-L-A  I or a pharmaceutically acceptable salt thereof wherein G isaryl, arylalkyl, heteroaryl, or heteroarylalkyl, which are optionallysubstituted by at least one R²; L is —O—, —C(O)—, —S(O)_(q)—, or—N(R³)—; A is

W is —C— or —N—; X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))—or —N(R⁸)—; Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; Z is a bond,—[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —CN, —NO₂,—N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; R² is independentlyselected from the group consisting of halogen, —SF₅, —CN, —NO₂,—N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;R³ is independently selected from the group consisting of H, alkyl andhaloalkyl; R⁴ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R⁵ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R⁶ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; R⁷ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituents selected from the group consisting ofhalo and —OR⁵; R¹¹ is independently selected from the group consistingof H, alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶ and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo and wherein each alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groupswhere R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or 3,provided that Y and Z cannot be a bond at the same time.
 2. A compoundaccording to claim 1 which is represented by the structural formula

or a pharmaceutically acceptable salt thereof, G is aryl, arylalkyl,heteroaryl, or heteroarylalkyl, which is optionally substituted by atleast one R²; L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—; W is —C— or —N—;X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or —N(R⁸)—; Y isa bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; Z is a bond,—[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —CN, —NO₂,—N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; R² is independentlyhalogen, —SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl,cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl,heteroaryl, heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl,alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy,aryl, arylalkyl, heteroaryl, and heteroarylalkyl are optionallysubstituted with one or more groups selected from the group consistingof —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, andcycloalkyl; R³ is independently selected from the group consisting of H,alkyl and haloalkyl; R⁴ is independently selected from the groupconsisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁵ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁶ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituent selected from the group consisting of haloand —OR⁵; R¹¹ is independently selected from the group consisting of H,alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶ and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo and wherein each alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groupswhere R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or 3,provided that Y and Z cannot both be a bond at the same time.
 3. Acompound according to claim 1 which represented by the structuralFormula

or a pharmaceutically acceptable salt thereof, G is aryl, arylalkyl,heteroaryl, or heteroarylalkyl, which is optionally substituted by atleast one R²; L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—; W is —C— or —N—;X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or —N(R⁸)—; Y isa bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; Z is a bond,—[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —CN, —NO₂,—N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl, andcycloalkylalkoxy are optionally substituted with one or more groupsselected from the group consisting of —OH, halo, alkyl, —S(O)_(q)-alkyl,haloalkyl, alkoxy, haloalkoxy, and cycloalkyl; R² is independentlyselected from the group consisting of halogen, —SF₅, —CN, —NO₂,—N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, cycloalkylalkoxy, aryl, arylalkyl, heteroaryl,heteroarylalkyl and —S(O)_(q)-alkyl, wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, and heteroarylalkyl are optionally substitutedwith one or more groups selected from the group consisting of —OH, halo,alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy, haloalkoxy, and cycloalkyl;R³ is independently selected from the group consisting of H, alkyl andhaloalkyl; R⁴ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R⁵ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; R⁶ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl and heteroarylalkyl; R⁷ isindependently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituent selected from the group consisting of haloand —OR⁵; R¹¹ is independently selected from the group consisting of H,alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶ and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —N(R⁵)(R⁶), —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, and halo and wherein each alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groupswhere R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or 3,provided that Y and Z cannot both be a bond at the same time.
 4. Thecompound according to claim 2 which is represented by the structuralformula

or a pharmaceutically acceptable salt thereof wherein G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is optionally substitutedby at least one R²; L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—; W is —C—or —N—; Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —S(O)_(q)-alkyl,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy,cycloalkl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, —S(O)_(q)-alkyl, alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R² is independently selected from the groupconsisting of halogen, —SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, heteroarylalkyl and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R³ is independently selected from the groupconsisting of H, alkyl, haloalkyl; R⁴ is independently selected from thegroup consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁵ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁶ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituent selected from the group consisting of haloand —OR⁵; R¹¹ is independently selected from the group consisting of H,alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶, and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein eachalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or
 3. 5. Thecompound according to claim 4 wherein W is —CH—.
 6. The compoundaccording to claim 5 wherein R is

and R⁸ is H or —(C₁-C₄)alkyl.
 7. The compound according to claim 6,wherein Y is —CH₂—.
 8. The compound according to claim 2 which isrepresented by the structural formula

or a pharmaceutically acceptable salt thereof wherein G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is optionally substitutedby at least one R²; L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—; W is —C—or —N—; X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or—N(R⁸)—; Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —S(O)_(q)-alkyl,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, —S(O)_(q)-alkyl, alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R² is independently selected from the groupconsisting of halogen, —SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, heteroarylalkyl and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R³ is independently selected from the groupconsisting of H, alkyl, haloalkyl; R⁴ is independently selected from thegroup consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁵ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁶ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituent selected from the group consisting of haloand —OR⁵; R¹¹ is independently selected from the group consisting of H,alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶, and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein eachalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or
 3. 9. Thecompound of claim 8 wherein W is —CH—.
 10. The compound of claim 9wherein R is

and R⁸ is H or —(C₁-C₄)alkyl.
 11. The compound according to claim 10,wherein X is —O— and Y is —CH₂—.
 12. The compound according to claim 3which is represented by the structural formula

or a pharmaceutically acceptable salt thereof wherein G is aryl, arylalkyl, heteroaryl, or heteroarylalkyl, which is optionally substitutedby at least one R²; L is —O—, —C(O)—, —S(O)_(q)—, or —N(R³)—; W is —C—or —N—; X is a bond, —O—, —C(O)—, —S(O)_(q), —C(R^(a))(R^(b))— or—N(R⁸)—; Y is a bond, —[C(R^(a))(R^(b))]_(n)—O—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—C(O)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(n)—S(O)_(q)—[C(R^(a))(R^(b))]_(n),—[C(R^(a))(R^(b))]_(m)— or —N(R⁸)—; R is a group selected from the groupconsisting of

and (v) tetrazolyl, wherein Q is —CH— or —N—, and J is —S—, —CH₂—, —O—or —N(R⁸)—; R^(a) is independently selected from the group consisting ofH, —OH, halo, alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R^(b) isindependently selected from the group consisting of H, —OH, halo,alkoxy, alkyl, cycloalkyl, and cycloalkylalkyl; R¹ is independentlyselected from the group consisting of H, halogen, —SF₅, —S(O)_(q)-alkyl,—CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy, cycloalkyl, cycloalkyloxy,cycloalkylalkyl, and cycloalkylalkoxy wherein said alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, and cycloalkylalkoxy areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, —S(O)_(q)-alkyl, alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R² is independently selected from the groupconsisting of halogen, —SF₅, —CN, —NO₂, —N(R⁶)(R⁷), —OH, alkyl, alkoxy,cycloalkyl, cycloalkyloxy, cycloalkylalkyl, cycloalkylalkoxy, aryl,arylalkyl, heteroaryl, heteroarylalkyl and —S(O)_(q)-alkyl, wherein saidalkyl, alkoxy, cycloalkyl, cycloalkyloxy, cycloalkylalkyl,cycloalkylalkoxy, aryl, arylalkyl, heteroaryl, and heteroarylalkyl areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, —S(O)_(q)-alkyl, haloalkyl, alkoxy,haloalkoxy, and cycloalkyl; R³ independently selected from the groupconsisting of H, alkyl, haloalkyl; R⁴ is independently selected from thegroup consisting of H, alkyl, cycloalkyl, cycloalkylalkyl, aryl,arylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁵ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, andheteroarylalkyl; R⁶ is independently selected from the group consistingof H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl and heteroarylalkyl;R⁷ is independently selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl; or R⁶ and R⁷together form a 4- to 7-membered heterocycloalkyl or a 5- or 5-memberedheteroaryl ring optionally having, in addition to the N atom, 1 or 2heteroatoms selected from the group consisting of O, N(R⁸), N or S,wherein said rings are optionally substituted by one or more R¹²moieties; R⁸ is independently selected from the group consisting of H,alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —C(O)—R⁵, —C(O)O—R⁵,—C(O)N(R⁶)(R⁷), —C(O)-alkylene-OR⁴, —C(O)-alkylene-N(R⁶)(R⁷),—C(O)-alkylene-S(O)_(q)—R⁵, —S(O)_(q)—R⁵, —S(O)_(q)-alkylene-OR⁴,—S(O)_(q)-alkylene-N(R⁶)(R⁷), -alkylene-OR⁴, -alkylene-S(O)_(q)—R⁵,-alkylene-N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷) wherein said alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl and alkylene areoptionally substituted with one or more groups selected from the groupconsisting of —OH, halo, alkyl, haloalkyl, alkoxy, haloalkoxy andcycloalkyl; R⁹ is independently selected from the group consisting of H,alkyl, haloalkyl; R¹⁰ is independently selected from the groupconsisting of H, —OH, alkyl, alkyl, cycloalkyl or alkoxy wherein saidalkyl, alkyl, cycloalkyl or alkoxy groups are optionally substitutedwith at least one substituent selected from the group consisting of haloand —OR⁵; R¹¹ is independently selected from the group consisting of H,alkyl, and haloalkyl; wherein each of the alkyl, cycloalkyl,cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl groups in R⁴, R⁵,R⁶, and R⁷ are independently unsubstituted or substituted by one or moreR¹² groups, where R¹² is independently selected from the groupconsisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl,heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, heteroarylalkyl,—OR⁴, —C(O)—R⁵, —C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and—S(O)₂N(R⁶)(R⁷), —NO₂, —SF₅, —CN, —N(R⁶)(R⁷) and halo and wherein eachalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl group in R¹² isindependently unsubstituted or substituted by one or more R¹³ groups,where R¹³ is independently selected from the group consisting of alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycloalkyl,heterocycloalkylalkyl, heteroaryl, heteroarylalkyl, —OR⁴, —C(O)—R⁵,—C(O)O—R⁵, —S(O)_(q)—R⁵, —C(O)N(R⁶)(R⁷), and —S(O)₂N(R⁶)(R⁷), —NO₂,—SF₅, —CN, and halo; m is independently 1, 2, or 3; n is independently0, 1 or 2; q is independently 0, 1, or 2; and p is 0, 1, 2, or
 3. 13.The compound according to 12, wherein W is —CH—.
 14. The compoundaccording to claim 13, wherein R is

and R⁸ is H or —(C₁-C₄)alkyl.
 15. The compound according to claim 14,wherein X is —O— and Y is —CH₂—.
 16. The compound according to claim 1which is a compound selected from the group consisting of

or a pharmaceutically acceptable salt thereof.
 17. A pharmaceuticalcomposition comprising a pharmaceutically effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.
 18. A method for controllinginsulin levels in a mammal in need thereof which comprises administeringan effective amount of a compound according to claim 1 or apharmaceutically acceptable salt thereof to said mammal.
 19. A methodfor the prevention or treatment of Type-2 diabetis mellitus in a mammalin need thereof which comprises administering an effective amount of acompound according to claim 1 or a pharmaceutically acceptable saltthereof to said mammal.
 20. A method for the prevention or treatment ofconditions related to Type-2 diabetis mellitus in a mammal in need thereof which comprises administering an effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof tosaid mammal.
 21. (canceled)